Xanthone derivatives

ABSTRACT

XANTHORNE DERIVATIVES OF THE FORMULA:   2-X,9-(O=),R1,R2-XANTHENE   IN WHICH X REPRESENTS A CARBOXYL OR 5-(1H)-TETRAZOLYL GROUP; AND R1 AND RI WHICH MAY BE THE SAME OR DIFFERENT EACH REPRESENT A HYDROGEN ATOM, AN ALKYL GROUP CONTAINING FROM 1 TO 4 CARBON ATOMS, A NITRO GROUP, A HALOGEN ATOM OR A GROUP OF THE FORMULA-NR3R4 OR OR3 OR NR5SO2R6 (IN WHICH THE GROUPS R2 AND R4 WHICH MAY BE THE SAME OR DIFFERENT EACH REPRESENT A HYDROGEN ATOM, A PHENYL GROUP, A BENZYL GROUP OR AN ALKYL GROUP WHICH MAY OPTIONALLY BE SUBSTITUTED BY AN ALKOXY GROUP CONTAINING FROM 1 TO 6 CARBON ATOMS, A PHENOXY GROUP, PHENYL GROUP, AN AMINO, ALKYLAMINO OR DIALKYLAMINO GROUP OR BY ONE OR MORE HYDROXY GROUPS; AND IN WHICH R5 IS A HYDROGEN ATOM OR AN ALKYL GROUP CONTAINING FROM 1 TO 6 CARBON ATOMS AND R6 IS AN ALKYL GROUP CONTAINING FROM 1 TO 6 CARBON ATOMS); WITH THE PROVISO THAT WHEN X REPRESENTS A CARBOXYL GROUP R1 AND R2 DO NOT BOTH REPRESENT HYDROGEN ATOMS; AND PHARMACEUTICALLY ACCEPTABLE NON-TONIX SALTS AND ESTERS OF SUCH COMPOUNDS. THESE DERIVATIVES HAVE PHARMACOLOGICAL ACTIVITY AND IT PARTICULAR INHIBIT THE RELEASE OF SPASMOGEN MEDIATORS FROM ANTIGEN-ANTIBODY REACTIONS.

United States Patent Office Patented Dec. 19, 1972 3,706,768 XANTHONEDERIVATIVES David Edmund Bays, London, England, assignor to Allen &Hanburys Limited, London, England No Drawing. Filed Nov. 17, 1970, Ser.No. 90,444 Claims priority, application Great Britain, Nov. 27, 1969,58,121/69 Int. Cl. C07d 7/44 US. Cl. 260-335 31 Claims ABSTRACT OF THEDISCLOSURE Xanthone derivatives of the formula:

in which X represents a carboxyl or 5-[lH1-tetrazolyl group; and R and Rwhich may be the same or different each represent a hydrogen atom, analkyl group containing from 1 to 4 carbon atoms, a nitro group, ahalogen atom or a group of the formula -NR R or 0R or NR SO R (in whichthe groups R and R; which may be the same or different each represent ahydrogen atom, a phenyl group, a benzyl group or an alkyl group'whichmay optionally be substituted by an alkoxy group containing from 1 to 6carbon atoms, a phenoxy group, phenyl group, an amino, alkylamino ordialkylamino group or by one or more hydroxy groups; and in which R, isa hydrogen atom or an alkyl group containing from 1 to 6 carbon atomsand R is an alkyl group containing from 1 to 6 carbon atoms); with theproviso that when X represents a carboxyl group R and R do not bothrepresent hydrogen atoms; and pharmaceutically acceptable non-toxicsalts and esters of such compounds.

These derivatives have pharmacological activity and in particularinhibit the release of spasmogen mediators from antigen-antibodyreactions.

0 R1 8 II 7 l LQ 0 R2 5 in which X represents a carboxyl or5-[lH]-tetrazolyl group; and R and R which may be the same or differenteach represent a hydrogen atom, an alkyl group containing from 1 to 4carbon atoms, a nitro group, a halogen atom or a group of the formula NRR or 0R or NR SO R (in which the groups R and R, which may be the sameor different each represent a hydrogen atom, a phenyl group, a benzylgroup or an alkyl group which may optionally be substituted by an alkoxygroup containing from 1 to 6 carbon atoms, a phenoxy group, phenylgroup, an amino alkylamino or dialkylamino group or by one of morehydroxy groups; and in which R is a hydrogen atom or an alkyl groupcontaining from 1 to 6 carbon atoms and R is an alkyl group containingfrom 1 to 6 carbon atoms); with the proviso that when X represents acarboxyl group R and R do not both represent hydrogen atoms; andpharmaceutically acceptable non-toxic salts and esters of suchcompounds.

Pharmaceutically acceptable non-toxic salts according to the inventionmay for example be salts of the group X with alkali metals, e.g. sodium,or with organic bases, for example dimethylaminoethanol and morpholine.Where R or R contain basic substituents the invention also providesnon-toxic salts with acids, e.g. hydrochlorides.

Also included are esters of the carboxylic acid function (X -COOI-l) forexample those with lower alkanols and glycerol.

Compounds according to the invention in which R, or R represent alkylare preferably those in which the alkyl groups contain from 1 to 4carbon atoms. Similarly where R, or R represent NR R OR or NR SO R and RR R and R represent alkyl groups these are preferably ones which containfrom 1 to 4 carbon atoms.

Specific preferred compounds are as follows:

7-nitro-9-oxo-xanthene-2-carboxylic acid.7-amino-9-oxo-xanthene-2-carboxylic acid, hydrochloride.6-nitro-9-oxo-xanthene-2-carboxylic acid.6-methoxy-9-oxo-xanthene-Z-carboxylic acid.6-propoxy-9-oxo-xanthene2-carboxylic acid.6-(2-hydroXyethoxy)-9-oxo-xanthene-Z-carboxylic acid.6-(2-hydroxypropoxy)-9-oxo-xanthene-2-carboxylic acid. 6-Z-methoxyethoxy -9-oxo-xanthene-2-carboxylic acid.6-(Z-dimethylaminoethoxy)-9-oxoXanthene-2-carboxylic acid.6-(isopropoxy)-9-oxoxanthene-Z-carboxylic acid. 6- 2 Z-hydroxyethoxyethoxy] -9-oxo-xanthenc-2-carboxylic acid. 6-(2-phenoxyethoxy)-9-ox0-Xanthene-2-carboxylic acid.6-.(Z-phenylethoxy)-9-oXo-xanthene-Z-carboxylic acid.6-phenoxy-9-oxo-xanthene-2-carboxylic acid.6-benzyloxy-9-oxo-xanthene-2-carboxylic acid.6-methoxy-7-nitro-9-oXo-xanthene-2-carboxylic acid.5-methoXy-9-oXo-xanthene-Z-carboxylic acid.7-methyl-9-oxo-xanthene-2-carboxylic acid.6,7-dimethoxy-9-oxo-xanthene-2-carboxylic acid.7-methoXy-9-oxo-xanthene-2-carboxylic acid and sodium salt.7-dimethylamino-9-oxo-xanthene-2-carboxylic acid.7-(N-methylamino)-9-oxo-xanthene-Z-carboxylic acid.7-hydroXy-9-oxo-Xanthene-2-carboxylic acid and ethyl ester.7-amino-9-oxo-xanthene-2-carboxylic acid and methyl ester.7-methanesulphonamido-9-oxo-xanthene-Z-carboxylic acid and methyl ester.7-dimethylamino-6-methoxy-9-oxo-xanthene-2-carboxylic acid.7-isopropoXy-9-oxo-xanthene-2-carboxylic acid.7-(2-hydroxyethoxy)-9-oxo-xanthene 2 carboxylic acid and sodium salt.7-chloro-9-oxo-xanthene-Z-carboxylic acid.6-chloro-9-0x0-xanthene-2-carboxy1ic acid.7-(N-methylmethanesulphonamido)-9-oxo-Xanthene- Z-carboxylic acid. 2-( 1H-tetrazol-S-yl -Xanthene-9-one. 6- 3-hydroxypropoxy -2-(lH-tetrazol-S-yl -xanthene- 9-one. 7-dimethylamino-2- lH-tetrazol-S-yl-xanthene-9-one. 6,7 -dimethoxy-2-( lH-tetrazol-S-yl -xanthene-9-one.7-methoxy-2-( lH-tetrazol-S-yl)-xanthene-9-one and sodium and morpholinesalt.

The xanthone derivatives according to the invention have been shown toinhibit release of spasmogens from antigen-antibody reactions such asoccur in the rat during the PCA (passive cutaneous anaphylaxis) testdescribed by Ogilvie (J. Immunol., 1967, 12, (2), 113). Thus thecompound of Example 24 when given intravenously was about 5-7 times morepotent than sodium cromoglycate in inhibiting the PCA reaction insensitised rats challenged with Nippostrongylis brasiliensis as antigen.These compounds are therefore of value in the treatment of conditions inwhich extrinsic antigen combination with a reaginic antibody isprimarily responsible, for example extrinsic asthma, hay fever,urticaria, eczema or atopic dermatitis.

The invention also provides pharmaceutical compositions which contain axanthone derivative of general Formula I or a salt or ester thereoftogether with a pharmaceutically acceptable carrier, excipient or otherformulatory agent. The compositions may also contain supplementarymedicinal agents, e.g. a bronchodilator, antihistamine, tranquilliser oranxio lytic. Forms for oral administration include tablets, capsules,syrups or emulsions.

For administration by inhalation the compositions according to theinvention may be in the form of a powder or snuff or as an aerosol spraypresentation. The last may conveniently be a pressurised pack with ametering valve to deliver a fixed dosage unit or may be an aqueoussolution that may be delivered via a nebuliser device.

The dosage at which the active ingredient is administered may varywithin a wide range. A suitable oral dosage range is generally from20-1500 mg. and for inhalation is from 1-20 mg.

The invention also provides a process for the preparation of compoundsof Formula I in which acids of general Formula II are cyclised toxanthones of general Formula 111 where R R and Z may be the groups R7 COH R7 R R and X of Formula I as herein defined or are groups that can besubsequently converted thereto by standard methods of chemistry wellknown to those skilled in the art, e.g. Z may be a methyl group whichcan then be oxidised to the carboxylic acid, or may be a nitrile whichcan be hydrolysed to the acid or can be converted into the-[lH]-tetrazolyl function. The cyclisation may be effected by heatingwith condensing agents such as sulphuric acid, phosphorus oxychloride,or polyphosphoric acid PPA), for example at temperatures between 60 and100". Where Z represents a nitrile group this is converted by -PPA underthe cyclisation conditions into an amide and by sulphuric acid into amixture of the amide and the acid. The amide can then be hydrolysed tothe carboxylic acid with mineral acids or with alkali or it may bereconverted into the nitrile with dehydrating agents, e.g. by warmingwith tosyl chloride and pyridine in dimethylformamide.

Conversion of compounds where Z represents a nitrile function into thosewhere Z represents a 5-[1H]-tetrazolyl group can be effected bytreatment with hydrazoic acid or its salts. The reaction canconveniently be carried out with sodium or ammonium azide in an inertsolvent, e.g. dimethylforrnamide, which may be warmed to about 100 C.

The intermediates of general Formula II may be prepared by an Ullmanreaction of the halo acid (IV) and a phenol (V).

COzH -Z Hal HO Hal represents a halogen atom, e.g. chlorine or bromine.The reaction can conveniently be carried out in the presence of analkali metal carbonate such as potassium carbonate, cuprous iodide, andcopper bronze at elevated temperatures, e.g. between and 180 C. Inerthighboiling solvents such as xylene or nitrobenzene may also be present.

Compounds of general Formula I wherein R and R are alkoxy may beprepared from an appropriate nitro or chloro xanthone carboxylic acid ornitrile of Formula VI by direct displacement e.g. as shown below:

dimethylformamide NaOMe The nitro or chloro group is in the 6 or 8position.

Compounds of general Formula I wherein R and/or R represent amino groupsmay be prepared by reduction of the corresponding nitro compounds with,for example stannous chloride. When X is a protected carboxyl group, forexample the group CO CH the compounds of general Formula I in which Rrepresents the group NHSO R may be prepared by reaction of theappropriate amine with a suitable sulphonyl chloride, for examplemethane sulphonyl chloride. Further alkylation may be effected with asuitable alkylating agent, for example dimethylsulphate. The ester, X=COCH may be hydrolysed to the acid, X=CO H by heating with sodiumhydroxide.

In the case where R, and/or R represent a group 0R an alternative to thedirect alkoxide displacement referred to above is reaction of thecompound in which R and R are hydroxyl and X is a protected carboxylgroup with an alkyl halide and an alkali e.g. sodium hydride withsubsequent hydrolysis of the protected group. Where R in the group ORrepresents an alkyl radical substituted with hydroxyl such radical maybe provided by reaction of the corresponding compound in which R, and/orR represent OH with an alkylene oxide in particular ethylene oxide.

The compound in which R and/or R represent OH may be prepared from itscorresponding compound in which R and/or R represent OCH by heating withhydrogen bromide in acetic acid or aluminum chloride in xylene.

The following examples illustrate the invention:

EXAMPLE 1 7-nitro-9-oxo-xanthene-2-carboxylic acid2-chloro-5-nitro-benzoic acid (20 g.), p-cresol (20 g.), anhydrouspotassium carbonate (1.4 g.), copper bronze (0.2 g.), and cuprous iodide(0.2 g.) were ground together and heated for 1 hour at -175". Themixture was cooled, triturated with water, and filtered. The filtratewas acidified with dilute hydrchloric acid and the precipitate wasrecrystallised from aqueous methanol (1:1) to give5-nitro-2-(p-tolyloxy)-benzoic acid (5 g.), M.P. 166-167".

The above acid g.) was heated at 95 C. with concentrated sulphuric acid(200 ml.) for 1 hour and then poured onto ice and filtered. Thefiilter-cake was suspended in water, treated with saturated aqueoussodium bicarbonate to pH 6, and re-filtered. The product wasrecrystallised from acetic acid to give Z-methyl-7-nitro-xanthone (14.1g.), M.P. 223.5-224 C.

The above xanthone (5 g.) in acetic acid-acetic anhydride (1:1) (200ml.) was treated slowly at C. with chromic oxide (5 g.) in the samesolvent mixture (100 ml.). After 9 hours at -75 the mixture was pouredinto water (100 ml.) and the precipitate was recrystallised from glacialacetic acid to give 7-nitro-9-oxo-xanthene-2- carboxylic acid (3.5 g.),M.P. 318.

EXAMPLE 2 7-amino-9-oxo-xanthene-2-carboxylic acid 7 nitro 9 oxoXanthene 2 carboxylic acid (5 g.) from Example 1 was added over 0.5 hourto stannous chloride (30 g.) in concentrated hydrochloric acid (30 ml.)at -100 C. and the mixture was kept at this temperature for a further 2hours. The precipitate was filtered off, washed with water, and stirredfor 0.5 hour with 5 N sodium hydroxide (175 ml.). The bright-yellowprecipitate was filtered off, dried, and recrystallised from ethanol.Treatment with an excess of 2 N-hydrochloric acid gave7-amino-9-oxo-xanthene-Z-carboxylic acid, hydrochloride (2.9 g.), M.P.400 C.

EXAMPLE 3 6-nitro-9-oxo-xanthene-2-carboxylic acid2-chloro-4-nitro-benzoic acid (10 g.), 4-hydroxy benzonitrile (11.9 g.),potassium carbonate (10.5 g.), copper bronze (0.1 g.) and cuprous iodide(0.1 g.) were ground together and placed in an oil-bath at 130. Thetemperature was raised to 170 and maintained at 170-180 for 1.5 hours.The cooled melt was powdered and extracted with water and the extractswere acidified with hydrochloric acid. The precipitate was washed withhot water, dried and recrystallised first from aqueous ethanol and thenfrom ethanol to give 2-(4-cyanophenoxy)-4-nitrobenzoic acid (4.8 g.),M.P. 185 C.

The above nitrile (4.6 g.) was refluxed in phosphorus oxychloride (50ml.) for 3.5 hours and the solution was then poured cautiously ontocrushed ice. The precipitate was washed with not aqueous potassiumcarbonate and then with water and recrystallised from glacial aceticacid to give 6-nitro-9-oxo-xanthene-2-carbonitrile (2.15 g.), M.P.285287.5 C.

The nitrile (1.6 g.) was refluxed with sulphuric acid (16 ml.), aceticacid (16 ml.) and water (16 ml.), for 2 hours. The mixture was pouredonto ice and the filtered product was recrystallised from glacial aceticacid to give 6-nitro-9-oxcrxanthene-Z-carboxylic acid (0.55 g.), M.P.300 C.

EXAMPLE 4 6-methoxy-9-oxo-xanthene-2-carboxylic acid6-nitro-9-oXo-xanthene-2-carboxylic acid (1 g.) from Example 3 indimethylformamide ml.) was heated at 8090 for 1.75 hours with sodiummethoxide [from sodium (0.25 g.) and methanol (10.5 ml.)] and thenpoured onto ice (300 g.) and extracted with ethyl acetate (350 ml.). Theaqueous phase was acidified with concentrated hydrochloric acid andchilled. The bufl precipitate was filtered ofl" and recrystallised fromglacial acetic acid to give 6-methoxy-9-oxo-xanthene-Z-carboxylic acid(0.45 g.), M.P. 331334.

The following 6-substituted-9-oxo-xanthene-2-carboxylic acids wereprepared from the 6-nitro compound as described above by displacementwith the appropriate alkoxide M.P. C. 6-propoxy- 2856-(2-hydroxyethoxy)- 280 6- 2-hydroxypropoxy 240 6-(2-methoxyethoxy)-260 6-(2-dimethylaminoethoxy)- 1 286 6-(isopropoxy)- 273 6- [2(2-hydroxyethoxy)ethoxy1- 235 6-(2-phenoxyethoxy)- 2876-(2-phenylethoxy)- 230 6-phenoxy- 198-201 6-benzyloxy- 291-293 1Hydrochloride.

EXAMPLE 5 6-methoxy-7-nitro-9-oxo-xanthene-2-carboxylic acid2-chloro-4-nitrobenzoic acid was dissolved in nitric acid (sp. gr. 1.5,30 ml.) and concentrated sulphuric acid (200 ml.) and the mixture washeated at 90-95 for 10 minutes. An exothermic reaction then began andthe temperaature rapidly rose to The reaction mixture was cooled to 100and kept at 90-100 for 20 minutes, and then poured onto crushed ice.2-chloro-4,5-dinitrobenzoic acid separated as an oil-White solid, thiswas collected and dried, M.P. 162-165 (46.8 g.).

A solution of potassium hydroxide (104.9 g.) in methanol (1 litre) wasadded over 10 minutes to 2-chloro- 4,5-dinitrobenzoic acid (209.9 g.) inmethanol (1 litre) stirred at 50. The mixture was stirred at 5055 for 30minutes. Water (2 litres) was then added and the yellow solutionacidified. The methoxy acid was recrystallised from methanol to giveneedles, M.P. 239-243 C. (107.9 g.) M.P. 235 C.

A mixture of 2-chloro-5-nitro-4-methoxy-benzoic acid (10.0 g., 0.0432mole) 4-hydroxybenzonitrile (11.6 g., 0.0973 mole), anhydrous potassiumcarbonate (6.8 g., 0.0493 mole), cuprous iodide (0.4 g.) and copperpowder (0.4 g.) was intimately ground in a mortar and then placed in anoil bath at The temperature was raised to over 15 minutes, and thenmaintained at this period for 1% hours. The yellowish-green melt wascooled and then taken up in water (1 litre). The solution was filteredto remove insoluble solids and acidified to pH 1. A faint yellow oilseparated. This slowly crystallised, was collected and dried, M.P.197-212 C. (8.65 g.). Recrystallisation from aqueous ethanol aflordedlight buff prisms, M.P. 216-2l9 C. (7.25 g.), of 2-(4-cyanophenoxy-4-methoxy-5-nitrobenzoic acid.

A solution of 2-(4-cyanophenoxy)-4-methoxy-5-nitrobenzoic acid (2.0 g.)in phosphorus oxychloride (20 ml.) was boiled under reflux for 35minutes. A light yellow solid separated during this period. The mixturewas cooled and poured onto crushed ice. A faint yellow solid separated,was collected and dried, M.P. 335337 C. (dec.) (1.7 g.).Recrystallisation from dimethylformamide gave light yellow prisms, M.P.339-340 C. (dec.), of 6-methoxy-7-nitro-9-oxo-xanthene-2-carbonitrile.

6-methoxy-7-nitro 9 oxo-xanthene 2 carbonitrile (2.093 g.) was suspendedin a solution of glacial acetic acid (20 ml.), water (220 ml.) andconcentrated sulphuric acid (20 ml.) and the mixture was boiled underreflux for 6 hours. During this period the product separated as a whitesolid. Water (100 ml.) was added and the precipitated solid wascollected, washed well with water and dried, M.P. 345.6-346 C. (dec.)(2.012 g.). Recrystallisation from dimethylformamide aflorded fineneedles, M.P. 341343 (dec.) (1.863 g.).

EXAMPLE 6 5-methoxy-9-oxo-xanthene-2-carboxylic acid2-chloro-S-methyl-benzoic acid (9.2 g.), 2-methoxyphenol (7.57 g.),copper bronze (l g.) were added to methanolic sodium methoxide [fromsodium (2.78 g.) and methanol (50 ml.)]. The solvent was removed and theresidue was placed in an oil bath at 140. The temperature was thenraised to 185, nitrobenzene (25 ml.) added, and heating continued for1.5 hours. The cooled mixture was treated with an excess of aqueouspotassium carbonate and extracted with ether.

The aqueous phase was adjusted to pH 8, filtered, and then acidifiedwith hydrochloric acid. Recrystallisation of the precipitate fromethanol gave 2-(2-methoxy-phenoxy)- S-methylbenzoic acid (6.1 g.), M.P.115.

Potassium permanganate (13.4 g.) and magnesium sulphate (3.7 g.) in hotwater (220 ml.) was added over 1.5 hours to the above acid (6.1 g.) inrefluxing 2 N sodium carbonate. After a further hour the excess ofpermanganate was discharged with sodium bisulphite and inorganic saltswere removed by filtration. The filtrate was acidified and theprecipitate was recrystallised from ethanol to give4-(2-methoxyphenoxy)-isophthalic acid (5.2 g.), M.P. 237-s c.

This acid (5.2 g.) was stirred at 90l00 C. for 1.5 hours withpolyphosphoric acid (79 g.) and poured into water (200 ml.). Theprecipitate was washed with water and recrystallised from ethanol togive 5-methoxy-9-oxoxanthene-Z-carboxylic acid (1.2 g.), M.P. 320 C.

EXAMPLE 7 7-methyl-9-oxo-xanthene-2-carboxylic acid2-(4-cyano-phenoxy)-5-methylbenzoic acid, M.P. 172, was obtained from2-chloro-S-methyl-benzoic acid and 4- hydroxybenzonitrile using themethod described in Example 6 for the preparation of2-(2-methoxy-phenoxy)- S-methylbenzoic acid.

The cyano acid (4.7 g.) was refluxed for 1.5 hours with sulphuric acid(47 ml.), acetic acid (47 ml.), and water (47 ml.). The mixture waspoured into water to give a precipitate of 5-methyl-2,4'-oxydibenzoicacid (4.5 g.), M.P. 263.

This di-acid (4.3 g.) was stirred at 90-100 for 2.5 hours withpolyphosphoric acid (57.3 g.) and then treated with water (50 ml.). Theprecipitate was washed with water and recrystallised from ethanol andthen from acetone to give 7-methyl-9-oxo-xanthene-Z-carboxylic acid (0.9g.), M.P. 298 C.

EXAMPLE 8 6,7-dimethoxy-9-oxo-xanthene-Z-carboxylic acid2-(4-cyanophenoxy)-4,5-dimethoxy-benzoic acid, M.P. 254-5 C., wasprepared from the Ullman reaction between 2-bromo-4,S-dimethoxybenzoicacid and 4-hydroxy benzonitrile using the conditions described inExample 6 for the synthesis of 2-(2-methoxyphenoxy)-5-methyl-benzoicacid.

The cyano-acid (1 g.) was heated at 90-100 for 25.5 hours withpolyphosphoric acid (6 g.) and then poured onto ice. The precipitate wasrecrystallised from acetic acid to give6,7-dimethoxy-9-oxo-xanthene-Z-carboxamide (0.95 g.), M.P. 2l9-222 C.

The preceding amide (0.5 g.) was heated at 90-95 for 27 hours withethanol (2.5 ml.) and 2 N sodium hydroxide (2.5 ml.). The solution wasacidified with concentrated hydrochloric acid and the precipitate wasrecrystallised from dimethylformamide to give 6,7-dimethoxy-9-oxo-xanthene-2-carboxylic acid (0.32 g.), M.P. 300 C.

EXAMPLE 9 7-methoxy-9-oxo-xanthene-Z-carboxylic acid Method A:2-chloro-5-nitro-benzoic acid (156 g.) in n-pentanol (600 ml.) andp-methoxyphenol (110 g.) were refluxed with stirring for 4 hours withanhydrous potassium carbonate (240 g.), copper bronze (0.8 g.) andcuprous iodide (0.8 g.). The cooled mixture was treated with ether andwater and the aqueous phase was further extracted with ether and thenacidified with dilute hydrochloric acid.

Extraction with ethyl acetate and dilution of the organic extracts withlight petroleum (B.P. 4080 C.) gave a fawn solid which onrecrystallisation from ethanol gave 2-(4-methoxyphenoxy)-5-nitro-benzoic acid (75 g.), M.P. 141.5 C.

This acid (75 g.) was cyclised with sulphuric acid by the methoddescribed in Example 1 for 5-nitro-2-(p-tolyloxy)-benzoic acid, to give7-methoxy-2-nitro-xanthone (37.2 g.), M.P. 211-2l2.5 C. aftercrystallisation from ethyl acetate/ methanol.

The nitro group was reduced to the primary amine with stannous chlorideusing the method described in Example 2. 7-methoxy-2-amino-xanthone,M.P. 181, was obtained by crystallisation from aqueous ethanol.

This amine (1.8 g.), suspended in concentrated hydrochloric acid (5 ml.)and water (10 ml.), was treated dropwise at below 5 C. with 10% sodiumnitrite (5 ml.). After ten minutes the mixture was added to a vigorouslyboiling solution of nickel chloride hexahydrate (3 g.) and sodiumcyanide (3 g.) in water (30 ml.). After 0.5 hour reflux, the mixture wascooled and filtered. The filter cake was washed well with water and thenrefluxed for 5 hours with sulphuric acid (25 ml.), acetic acid (25 ml.)and water (25 ml.). The mixture was poured into water and filtered. Thecake was taken up in an excess of 8% sodium bicarbonate, filtered, andreprecipitated by acidification with hydrochloric acid.Recrystallisation from water acetic acid (1:5) gave7-methoxy-9-oxo-xanthene-2-carboxylic acid (0.65 g.), M.P. 297-297.5 C.

Method B: 2-bromo-5-methoxybenzoic acid (924 g.), potassium carbonate(818 g.), copper bronze (16 g.), cuprous iodide (16 g.), and xylene (4l.) were stirred at and 4-hydroxybenzonitrile (476 g.) was added over 10minutes. The temperature was raised to C. for 3 hours during which timean azeotrope of water (200 ml.) and xylene was collected. The mixturewas cooled to 100 C. and water (3 l.) was added. After filtrationthrough Hyflo the xylene layer was washed with water (2 l.). Thecombined aqueous phases were slowly added to vigorously stirredconcentrated hydrochloric acid 1200 ml.). The solid was collected,washed with water, slurried with hot water, and filtered hot to givecrude 2-(4-cyanophenoxy)-5-methoxy-benzoic acid (780 g.), M.P. 154- 155C. Recrystallisation from aqueous ethanol gave material M.P. 171-2 C.

The above nitrile (100 g.) and concentrated sulphuric acid (300 ml.)were heated at 90-100" C. for 0.5 hours. Acetic acid (200 ml.) and water(300 ml.) were added and the mixture was refluxed for 4 hours and pouredinto water (1 1.). The precipitate was recrystallised fromdimethylformamide to give 7-methoxy-9-oxo-xanthene-Z- carboxylic acid(52 g.), M.P. 301-302".

The above acid (48 g.) was stirred with water (250 ml.) at 90 anddimethylaminoethanol (17.5 g.) was added. The solution was added tosodium hydroxide (7.25 g.) in water (35 ml.). Ethanol Was added and theprecipitate was washed with ethanol and dried at 50 C. to give thesodium salt, monohydrate, of the acid.

Method C: 2 (4 cyanophenoxy)-5-methoxy-benzoic acid (400 g.) (Method Babove) and polyphosphoric acid g.) was heated for 2 hours at 90-100 C.Acetic acid (150 ml.) was added and the mixture poured into water (41.), keeping the temperatures below 45 C. The solid was washed well withwater and then with ethanol and dried at 60 to give7-methoxy-9-oxo-xanthene-2-car boxamide (358 g.), M.P. 280-290 C.crystallisation from aqueous acetic acid gave material M.P. 301-3 C.

The above carboxamide (10 g.) was refluxed for 4 hours in water (30ml.), glacial acetic acid (30 ml.), and concentrated sulphuric acid (30ml.). The mixture was cooled and filtered to give7-methoxy-9-oxo-xanthene-2- carboxylic acid (9 g.), M.P. 2969 C.

9 EXAMPLE 10 7-dimethylarnino-9-oxo-xanthene-2-carb0xylic acid2-chloro-5-nitro-benzoic acid (10 g.) and p-hydroxy benzonitrile (11.9g.) were condensed, using the method described in Example 1 for5-nitro-2-(p-tolyloxy)-benzoic acid, to give2-(4-cyanophenoxy)-5-nitro-benzoic acid (6.1 g.), M.P. 180-1825, aftercrystallisation from aqueous ethanol.

The above acid (48.8 g.) was cyclised with phosphorus oxychloride, asdescribed in Example 3 for 6-nitro-9-oxoxanthene-Z-carbonitrile, to give7-nitro-9-oxo-xanthene-2- carbonitrile, M.P. 315-319.

This nitro compound (3 g.) was reduced to the primary amine withstannous chloride, as described in Example 2 for7-amino-9-oxo-xanthene-2-carbonitrile (1.6 g.), M.P. 271-276.

The above amine (1.5 g.) in dioxan (10 ml.) was treated with formic acid(12 ml.) and formaldehyde (37%) (1.65 g.) at room temperature and thenheated at 95-l00 C. for 5 hours. On cooling to C. a solid separated thatwas purified by elution from a column of alumina with ethyl acetatebenzene. Recrystallisation from ethanol gave7-dirnethylamino-9-oxo-xanthene-2 carbonitrile (0.49 g.).

This nitrile (0.42 g.) was hydrolysed with watersulphuric acid-aceticacid, as described in Example 3 for 6-nitro-9-oxo-xanthene-Z-carboxylicacid, to give 7-dimethylamino-9-oxo-xanthene-2-carboxylic acid (0.37g.), M.P. 280-281.5 C., after crystallisation from ethanol.

EXAMPLE l1 7- N-methylamino -9-oxo-xanthene-2-carboxylic acid7-(N-methyl methanesulphonamido)-9-oxo-xanthene- 2-carboxylic acid,methyl ester (290 mg.) was heated under reflux with stirring in glacialacetic acid (2.9 ml.), concentrated sulphuric acid (2.9 ml.) and water(2.9 ml.) for 2% hours. The brown solution was left to cool, then addedto ice and cooled in an ice bath. The precipitate was filtered off andrecrystallised from aqueous dimethylformamide. Yield: 176 mg. M.P.274.5-276 C.

EXAMPLE 12 7-hydroxy-9-oxo-xanthene-2-carboxylic acid7-methoxy-9-oxo-xanthene-2-carboxylic acid (0.6 g.), aluminum chloride(2.4 g.) and xylene (20 ml.) were heated at 65-75 C. for 5 hours andpoured onto crushed ice (50 g.) and concentrated hydrochloric acid (15ml.). The precipitate was filtered off, taken up in 8% sodiumbicarbonate, refiltered and recovered by acidification with hydrochloricacid. The product was extracted into ethyl acetate and the extracts werewashed and evaporated. Crystallisation of the residue from ethyl acetategave 7- hydroxy-9-oxo-xanthene-Z-carboxylic acid (0.2 g.), M.P. 349 C.(d).

EXAMPLE 13 7-amino-9-oxo-xanthene-2-carboxylic acid methyl ester7-amino-9-oxo-xanthene-2 carboxylic acid, hydrochloride (12.2 g.), fromExample 2, was refluxed for 16 hours in methanol (1600 ml.) andsulphuric acid (61 m1.) and then poured onto crushed ice. Theprecipitate was filtered 01f, triturated with 2 N sodium hydroxide,refiltered, and dried to give the methyl ester (9.4 g.),

M.P. 252-4 C.

EXAMPLE 14 7-methanesulphonamido-9-oxo-xanthene-2-carboxylic acid7-amino-9-oxo-xanthene-2 carboxylic acid, methyl ester (4 g.), fromExample 13, pyridine (150 ml.), and methanesulphonyl chloride (1.28 ml.)were stirred for 6 days at room temperature and then for 24 hours at 40C. A further portion (1.05 ml.) of methanesulphonyl chloride was addedand heating continued for 5.5 hours.

10 The mixture was poured onto ice and the precipitate was crystallisedfrom aqueous acetone to give 7-methanesulphonamido 9 oxo-xanthene 2carboxylic acid, methyl ester (3.5 g.), M.P. 274276 C.

The above ester (0.3 g.), sodium hydroxide (0.076 g.), water (6 ml.) andethanol (3 ml.) were refluxed for 6 hours. The mixture was diluted,acidified with concentrated hydrochloric acid and chilled. Theprecipitate was recrystallised from dimethylformamide to give7-rnethanesulphonamido 9 oxo-xanthene-2-carboxylic acid (0.27 g.), M.P.321 (d).

EXAMPLE 15 7-dimethylamino-6-methoxy-9-oxo-xanthene-2- carboxylic acid 2chloro 4 rnethoxy 5 nitro-benzoic acid (10 g.) and 4-hydroxybenzonitrile(11.6 g.) were condensed, using the method described in Example 1 for5-nitro-2- (p-tolyloxy)benzoic acid, to give 2-(4-cyanophenoxy)-4-methoxy-S-nitrobenzoic acid (7.25 g.), M.P. 216-219", aftercrystallisation from aqueous ethanol.

This acid (2 g.) was cyclised with phosphorus oxychloride as describedin Example 3 for 6-nitro-9-oxoxanthene 2 carbonitrile, to give6-methoxy-7-nitro-9- oxo-xanthene 2 carbonitrile (1.7 g.), M.P. 339-340C. (d), after crystallisation from dimethylformamide.

The above nitrile g.) was reduced with stannous chloride, as describedin Example 2 for 7-amino-9-oxoxanthene-Z-carboxylic acid, to give6-methoxy-7-amino- 9-oxo-xanthene-2-carbonitrile (26.9 g.), M.P. 340 C.(d), after crystallisation from dimethylformamide.

This amine (2 g.) was treated with formic acid and Formalin as describedin Example 10 for 7-dimeth'ylamino-9-oxo-xanthene-Z-carbonitrile. Thereaction solution was concentrated and the precipitate was purified byelution from a column of alumina with 5-10% ethyl acetate/benzene togive 7-dimethylamino-6-methoxy-9- oxo-xanthene-Z-carbonitrile (0.94 g.),M.P. 224-7 C., after crystallisation from methylene chloride ethanol.

The above nitrile (0.7 g.) was refluxed for 2 hours in acetic acid (10ml.), sulphuric acid (10 ml.), and water (10 ml.). The solution wasdiluted with water (100 ml.) and adjusted to pH 4 with 2 N sodiumhydroxide. The precipitate was collected and recrystallised from aqueousdimethylformamide to give 7 dimethylamino-6-methoxy-9-oxo-xanthene-2-carboxylic acid (0.66 g.), M.P. 292-4 C.

EXAMPLE 16 7-isopropoxy-9-oxo-xanthene-2-carboxylic acid 7 hydroxy 9oxo-xanthene-2-carboxylic acid (7 g.) from Example 12 in dry ethanol(700 ml.) was refiuxed for 5 hours with dry hydrogen chloride, thencooled, and diluted with water (110 ml.). The precipitate wascrystallised from ethanol to give the ethyl ester (4 g.), M.P. 230 C.

This ester (0.5 g.) and sodium hydride (50% dispersion in oil) (0.3 g.)were stirred in dimethylforrnamide for ten minutes and isopropyl iodide(3 ml.) was added. After a further ten minutes the excess of hydride wasdecomposed with water and the solution was allowed to stand for 1 hour.The mixture was acidified and the precipitate was crystallised fromethanol to give 7-isopr0p0xy-9-oxoxanthene 2 carboxylic acid (0.22 g.),M.P. 269-270 C.

EXAMPLE 17 7-(2-hydroxyethoxy)-9-oxo-xanthene-2-carboxylic acid 7hydroxy 9 oxo-xanthene 2 carboxylic acid, ethyl ester (1 g.), fromExample 16, dimethylformamide (10 ml.), ethylene oxide (5 ml.), andpyridine (one drop) were heated in a sealed tube at for 116 hours andthen poured into water. The precipitate was refluxed for 2 hours withsodium hydroxide (l g.) ethanol (250 ml.), and water (10 ml.) and thesolution was cooled and acidified. The solid was crystallised fromethanol to give 7 (2 hydroxyethoxy) 9 oxo-xanthene-Z-carboxylic acid(0.19 g.), M.P. 263-265 C.

7-(2-hydroxyethoxy)-9-oxo-xanthene-2-carboxylic acid sodium salt 10%sodium hydroxide solution (1.9 ml.) was added to a suspension of7-(2-hydroxyethoxy)-9-oxo-xanthene- 2-carboxylic acid (1.5 g.) in water(10 ml.). The solution was heated to 70 C. and hot ethanol was added.The mixture was allowed to cool to give a crystalline sodium salt. Itwas filtered 01f, washed with ethanol and dried at 50 C., to give thesodium salt (1.4 g.).

EXAMPLE 1'8 7-chloro-9-oxo-xanthene-2-carboxylic acid2,5-dichlorobenzoic acid (23.5 g.), potassium carbonate (23 g.), cuprousiodide (0.1 g.), copper bronze (0.1 g.), 4 hydroxybenzonitrile (21.6g.), and nitrobenzene (105 ml.) were heated at 160 for 12 hours. Themixture was diluted with water and ether and the organic phase wasextracted with 2N sodium hydroxide. The alkaline extracts were acidifiedwith hydrochloric acid and the oil that separated was allowed to standuntil the unchanged 4 hydroxybenzonitrile crystallised, leaving thecrude 5-chloro-2-(4-cyanophenoxy)-benzoic acid.

The crude acid was cyclised with polyphosph-oric acid, as described inExample 9, Method C, for 7-mcthoxy- 9-oxo-xanthene-2-carboxamide, togive crude 7-chloro- 9 oxo-xanthene 2 carboxamide which was used in thenext stage.

The crude amide (0.5 g.) was refluxed for 7 days in acetic acid (50 ml.)and 2 N sulphuric acid (4 ml.). The mixture was diluted with water andthe precipitate was crystallised from acetic acid to give7-chloro-9-oxo-xanthene-2-carboxylic acid (0.05 g.), M.P. 349.5 C. (d).

The 6-chl0ro compound may be prepared in a similar manner M.P. 164.8 C.

EXAMPLE l9 7-(N-methyl-methanesulphonamido)-9-ox0xanthene- 2-carboxylicacid 7 methanesulphonamido 9 oxo-xanthene 2 carboxylic acid, methylester (2.93 g.) (Example 14) and dimethyl sulphate (2.4 ml.) werestirred for 5 hours with N sodium hydroxide (18.6 ml.). The solid wasfiltered off, washed with water, and extracted twice with dilute sodiumcarbonate. Acidification of the alkaline extracts and crystallisationfrom aqueous acetic acid gave 7-(N- methyl methanesulphonamido)-9-oxo-xanthene-2-carboxylic acid (0.76 g.), M.P.262.5-263.5 C.

EXAMPLE 20 2-( lH-tetrazol-S-yl)-xanthene-9-one (a) 4-cyanophenol (25g.), 2-chlorobenzoic acid (36.7 g.), copper bronze (0.35 g.) and cuprousiodide (0.35 g.) were added to methanol (200 ml.) containing sodium(10.7 g.). The solvent was removed in vacuo and the residue heated at185 for minutes. Boiling nitrobenzene (42 ml.) was added and thetemperature maintained at 180190 for 3 hours. It was cooled and thesolid residue dissolved in dilute potassium carbonate solution (500 ml.)filtered, washed with ether and acidified to ca. pH 6. The solution wasclarified by treatment with charcoal and acidified to pH 1. The solidwas filtered off and crystallised from aqueous ethanol to give2-(4-cyanophenoxy)-benzoic acid (23.5 g.), M.P. 138-9" (hemialcoholate).

2-(4-cyanophenoxy)-benzoic acid (2.39 g.), sodium azide (0.72 g.) andammonium chloride (0.59 g.) in dimethylformarnide (20 ml.) were heatedat for 26 hours. The mixture was cooled, filtered, and the solventremoved in vacuo. The residual oil was dissolved in dilute sodiumbicarbonate solution, acidified, and precipitated solid filtered off andcrystallised from aqueous ethanol to give2-[4-(lH-tetrazol-S-yl)-phenoxy]benzoic acid (1.2 g.) M.P. 219-221.

2-[4-(lH-tetrazol-S-yl)-phenoxy]benzoic acid (0.5 g.) in concentratedsulphuric acid (3 ml.) was heated at 100 for 2.95 hours, cooled andpoured onto ice. The precipitated solid was filtered off andcrystallised from dimethylctormamide to give the xanthone (0.16 g.) M.P.400.

(b) 2-[4-(lH-tetrazol-S-yl)-phenoxy]benzoic acid (0.5 g.) inpolyphosphoric acid (3 g.) was heated at 100 for 5.25 hours, cooled anddiluted with water. The precipitated solid was filtered off andcrystallised from dimethylformamide to give the xanthone (0.24 g.) M.P.400.

EXAMPLE 21 6-(3-hydroxypropoxy) -2-( lH-tetrazol-5-yl)xanthone6-nitro-9-oxo-xanthene-2-carbonitrile (4.5 g.) (Example 3) was stirredat room temperature for 3.5 hours with a solution of sodium (1.2 g.) inpropane-1,3-diol (51 ml.), then poured into water (700 ml.) andextracted with ethyl acetate (1500 ml.). The organic extracts wereevaporated and the residue poured onto ice. crystallisation of theprecipitate from aqueous ethanol and then from ethanol gave6-(3-hydroxypropoxy)-9-ox0-xanthene-2-carbonitrile (3.35 g.), M.P.l70171.5.

This nitrile (1.5 g.), sodium azide (0.37 g.), ammonium chloride (0.3g.) and dimethylformamide were heated at 100 for 7.5 hours then pouredonto ice. The mixture was extracted with ethyl acetate and the aqueousphase was acidified with concentrated hydrochloric acid and cooled to 0C. The precipitate was crystallised from dimethylformamide to give6-(3-hydroxypropoxy)-2-(1H- tetrazol-5-yl)-xanthone (1.2 g.) M.P. 280 C.

EXAMPLE 22 7-dimethylamino-2-( lH-tetrazol-S-yl -xanthone 7dimethylamino-9-oxo-xanthene-2-carbonitrile (0.24 g.) (Example 10),sodium azide (0.06 g.), ammonium chloride (0.05 g.) anddimethylformamide (4 ml.) were heated at 100 for 40 hours and thenevaporated to dryness. The residue was taken up in warm dilute sodiumbicarbonate and filtered. The filtrate was acidified with concentratedhydrochloric acid and cooled to 0 C. The precipitated solid was filteredoff and crystallised twice from aqueous ethanol to give7-dimethylamino-2-(1H- tetrazol-5-yl)-xanthone (0.1 g.), M.P. 267-2695C.

EXAMPLE 23 6,7-dimethoxy-2- lH-tetrazol-S-yl) -xanthone6,7-dimethoxy-9-oxo-xanthene-2-carboxamide (l g.) (Example 8), tosylchloride (1.4 g.), pyridine (1.38 ml.), and dimethylformamide (25 ml.)were warmed to 7580 C. for 3 hours and then poured onto crushed ice. Theprecipitate was crystallised from ethanol to give6,7-dimethoxy-9-oxo-xanthene-2-carbonitrile (0.67 g.).

The nitrile (0.5 g.) was treated with sodium azide, as described inExample 22 for 7-dimethylamino-2-(IH-tetrazol-5-yl)-xanthone, to give6,7-dimethoxy2-(lH-tetrazol-5-yl) xanthone (0.38 g.), M.P. 300, aftercrystallisation from aqueous dimethylformamide.

EXAMPLE 24 7-methoxy-2-( 1H-tetrazol-5 -yl) -xanthone7-methoxy-9-oxo-xanthene-2-carboxamide (285 g.) (Example 9, Method C),tosyl chloride (304 g.), pyridine (1150 ml.), and dimethylformamide(1150 ml.) were heated at 100 for hours and then poured onto crushed ice(3 kg.). The slurry was acidified with concentrated hydrochloric acid.The precipitate was washed with water (2X 1 l.) and dried at 50 C.crystallisation from dimethylformamide gave7-methoxy-9-oxo-xanthene-2-carbonitrile (202 g.), M.P. 255-8 C.

The above nitrile (225 g.), ammonium chloride (55 g.), sodium azide (65g.), and dimethylformamide (160 ml.) were heated for 6 hours at 115 C.and then poured into water (2 1.) containing concentrated hydrochloricacid. The precipitate was crystallised from dimethylformamide to give7-methoxy-2-(lH-tetrazol-S-yl)-Xanthone 190 g.), M.P. 282-3 C.

The above tetrazole (190 g.) was dissolved in warm water (800 ml.) whichcontained morpholine (62 ml.) and the solution was added to sodium (16.1g.) in ethanol (450 ml.).

Ethanol (1.5 l.) was added and the precipitate was washed with ethanoland dried at 45 C. to give the sodium salt, trihydrate (159 g.).

The tetrazole (127.5 g.) was dissolved in water (450 ml.) containingmorpholine (39.5 g.) by warming on the steam bath. Acetone (500 ml.) wasadded and the solid that crystallised was washed with acetone and driedto give the tetrazole, morpholine salt (99 g.), M.P. 285-8 C.

EXAMPLE 25 Mg. Active ingredient sodium salt, monohydrate 2.25Emulsifier YN 0.075 Propellant 11 23.10 Propellant 12 59.30

The active ingredient sodium salt is micronised and mixed with thepropellant 11 together with the Emulsifier YN. The required quantity ofthis suspension is filled into an aerosol can and a suitable meteringvalve crimped in place. The propellant 12 is filled into the can throughthe valve.

Example 26 Capsules: To prepare 5,000 capsules each containing mg. ofthe compound of Example 9 (active ingredient).

Mix 50 g. of finely powdered active ingredient together with sufficientmicrocrystalline cellulose to fill a No. 1 hard gelatin capsule so thateach capsule contains 10 mg. active ingredient.

Aerosols: An inhalation aerosol may be prepared containing in eachmetered dose 2 mg. of active ingredient made to the following formula:

Mg. Active ingredient sodium salt, trihydrate 2.6 Emulsifier YN 0.075Propellant ll 23.10 Propellant 12 59.30

The active ingredient sodium salt is micronised and mixed with thepropellant 11 together with the Emulsifier YN. The required quantity ofthis suspension is filled into an aerosol can and a suitable meteringvalve crimped in place. The propellant 12 is filled into the can throughthe valve.

14 What is claimed is: 1. A compound of the formula '1 2 coon in which Rand R are each H; alkyl of 1 to 4 C atoms; nitro; halo; hydroxy;phenoxy; alkoxy of 1 to 4 C atoms; alkoxy of l to 4 C atoms substitutedby hydroxy, alkoxy of 1 to 6 C atoms, Z-hydroxyethoxy, phenoxy, phenylor dialkylamino in which each alkyl radical is of 1 to 4 C atoms;monoalkylamino of 1 to 4 C atoms; dialkylamino in which each alkylradical is of 1 to 4 C atoms; alkanesulphonoamido of 1 to 6 C atoms orN-alkyl-substituted alkanesulphonamido in which the N-alkyl substituentand alkane moiety are of 1 to 6 C atoms, at least one of R and R beingother than H or a pharmaceutically acceptable non-toxic salt or loweralkyl or glyceryl ester thereof.

2. A compound as claimed in claim 1 which is 7-nitro-9-oxo-xanthene-Z-carboxylic acid.

3. A compound as claimed in claim 1 which is 6-nitro-9-oxo-xanthene-Z-carboxylic acid.

4. A compound as claimed in claim 1 which is6-methoxy-9-oxo-xanthene-2-carboxylic acid.

5. A compound as claimed in claim 1 which is6-propoxy-9-oxo-xanthene-2-carboxylic acid.

6. A compound as claimed in claim 1 which is 6-(2-hydroxyethoxy)-9-oxo-xanthene-2-carboxylic acid.

7. A compound as claimed in claim 1 which is 6-(2-hydroxypropoxy)-9-oxo-xanthene-2-carboxylic acid.

8. A compound as claimed in claim 1 which is 6-(2-methoxyethoxy)-9-oxo-xanthene-Z-carboxylic acid.

9. A compound as claimed in claim 1 which is6-(2-dimethylaminoethoxy)-9-oxo-xanthene 2 carboxylic acid,hydrochloride.

10. A compound as claimed in claim 1 which is6-(isopropoxy)-9-oxo-xanthene-2-carboxylic acid.

11. A compound as claimed in claim 1 which is 6-[2 (2hydroxyethoxy)ethoxy]-9-oxo-xanthene-2-carboxylic acid.

12. A compound as claimed in claim 1 which is 6-(2-phenoxyethoxy)-9-oxo-xanthene-2-carboxylic acid.

13. A compound as claimed in claim 1 which is 6-(2-phenylethoxy)-9-oxo-xanthene-2-carboxylic acid.

14 A compound as claimed in claim 1 which is 6-phenoxy-9-oxo-xanthene-Z-carboxylic acid.

15. A compound as claimed in claim 1 which is6-benzyloxy-9-oxo-xanthene-2-carboxylic acid.

16. A compound as claimed in claim 1 which is6-methoxy-7-nitro-9-oxo-xanthene-2-carboxylic acid.

17. A compound as claimed in claim 1 which isS-methoxy-9-oxo-xanthene-2-carboxylic acid.

18. A compound as claimed in claim 1 which is7-methyl-9-oxo-xanthene-2-carboxylic acid.

19. A compound as claimed in claim 1 which is 6,7-dimethoxy-9-oxo-xanthene-Z-carboxylic acid.

20. A compound as claimed in claim 1 which is7-methoxy-9-oxo-xanthene-2-carboxylic acid or its sodium salt.

21. A compound as claimed in claim 1 which is7-dimethylamino-9-oxo-xanthene-Z-carboxylic acid.

22. A compound as claimed in claim 1 which is 7-(N-methylamino)-9-oxo-xanthene-2-carboxylic acid.

23. A compound as claimed in claim 1 which is7-hydroxy-9-oxo-xanthene-2-carboxylic acid or its ethyl ester.

24. A compound as claimed in claim 1 which is 7- methanesulphonamido 9oxo xanthene 2 carboxylic acid or its methyl ester.

25. A compound as claimed in claim 1 which is 7-dimethylamino-G-methoxy9 oxo xanthene-Z-carboxylic acid.

26. A compound as claimed in claim 1 which is7-isopropoxy-9-oxo-xanthene-Z-carboxylic acid.

27. A compound as claimed in claim 1 which is 7-(2- References Citedhydroxyethoxy)-9-oxo-xanthene-Z-carboxylic acid.

28. A compound as claimed in claim 1 which is 7-chloro 9 oXo xamhene zcarboxylic acid. Chem cal Abstracts, vol. 20 (1926), p. 392.

29. A compound as claimed in claim 1 which is 6-ch10- 5 ChemlcalAbstracts 33 (1939), P- 8025' ro-9-oxo-xanthene-Z-carboxylic acid.

30. A compound as claimed in claim 1 which is 7-(N- NORMA MILESTONEPnmary Exammer ggaglyglc-gigianesulphonamido)-9-oxo-xanthene 2 car- Us.cl XR' 31. The sodium salt of the compound of claim 27. 10 260-303 465515 520 Chemical Abstracts, vol. 16 (1922), pp. 17567.

